1-[pyrimidinyl-(2)] guanazole compounds



f sustained vasodilation when administered to laboratory animals. AS

United States Patent 3,041,339 1-[PDINYL-(2)] GUANAZGLE QIGMPQUNDS Kenzo Sirakawa, Nishinomiya, Hyogo, Teruaki Tsujikawa, Otsu, Shiga, and Takashi Tsuda, Higashiyodogawa-ku, Osaka, Japan, assignors to Takeda Chemical Industries, Ltd., Osaka, Japan No Drawing. Filed July 28, 1961, Ser. No. 127,509 Claims priority, application Japan July 30, 1960 10 Claims. (Cl. Mil-256.4)

This invention relates to novel compounds useful as medicines for the therapy of hypertension. More particularly, the invention has a specific relation to new pyrimidinylguanazole compounds of the Formula I, some of which have characteristic effects in lowering blood pressure, and to the preparation of those compounds:

N R m-NN R: N i R HN N NHR R3 wherein each 'R and R stands for an alkoxyl group; R stands for alkyl or an alkoxyl group; for. hydrogen, an alkyl, an group.

in bodies of animals including human beings, a constriction of local blood vessels results in diminishing flow-rate of blood, and if the constriction is continued for some period it gives rise to oxygen and alimentary deficiency or necrosis at the part where the constriction occurs. While if tension of peripheral arterioles is elevated all over the body, there occurs so-called hypertension (hypertonia) in the body and it gives rise to various hindrances for the normal physiological function of the body, for example, headache, cardiac failure, or disturbance of circulation, and most dangerous of all, sudden death by cerebral vascular accident.

Hypertension is thought to be provoked by such factors as central nervous factor, autonomic nervous factor, renal factor, etc., and the respective medicaments affecting these factors have been known and used. However, no medicament has been known that directly afiects the peripheral vessels to allow them to dilate without any effect on the central or the autonomic nervous system.

On the other hand, the compounds of the present in vention, represented by 1-[pyfimidinyl-(Zfiguanazole, have the following characteristic properties as medicines against hypertension: namely, they cause a gradual and hypotensive effect due to a direct peripheral hydrogen, an alkyl or hydrogen, a halogen, an and each of R and R stands aryl or a carboxylic acid acyl the compounds have no direct influence on the nervous systems and possess a desirable oral efficacy and also are capable of dilating the coronary blood vessels, they may be safely and conveniently used for hypertensive patients Without causing sudden fall of blood pressure.

It is the object of the present invention to provide novel compounds of the Formula I, which have the above-mentioned characteristic effects as medicines for hypertension. They may be administered orally or by injection.

Another object of the invention is to provide means for producing the new compounds of the Formula 'I.

To realize the second object of the invention, a condensation reaction is effected between the starting matenials selected from the following combinations of compounds:

3,041,339 Patented June 26, 1962 (l) A compound representable by the Formula II N R1 TNHNH:

(III) R3 (IV) Where R R and R are of the same meanings as in Formula I and X is a halogen, and a compound representable by the Formula V wnN m Nnm v where R is of the same meanings as mentioned above and R" is hydrogen, a lower alkyl and an aryl; or

(3) A compound representable by the Formula VI CN-N where R and R are of the same meanings as mentioned above, and a compound selected from the group consisting of ll I where R R and R are of the same meanings as in Formula I, each of Y and Zis a member selected from the group consisting of =0, =NH, two halogen atoms, two lower alkoxyls and both a halogen atom and a lower alkoxyl, and W is a member selected from the group consisting of hydroxyl and a lower alkoxyl.

By the condensation reactions there can be produced the desired pyrimidinylguanazoles such as 1-[4-methylpyrimidiny1-(2) 1-3-amino-5-methylaminol 2,4) -triazole,

1- [4-methylpyrimidinyl-(2) 1 -3-amino-5-ethylamino-( 1,

2,4 triazole,

1-[4-methylpyrimidinyl- (2) 1-3-amino-5-isopropylamino- 1,2,4) -triazole,

1- [4-methylpyrirnidinyl- (2) 1 -3 amino-S-butylaminol ,2,

4 -triazole,

1-[4,6-dimethylpyrimidinyl- (2) 1 guanazole,

1- [4,6-dimethylpyrim-idinyl-(2) 1-3-amino-5-methylamino- 1,2,4) -triazole,

1 [4,6-dimethylpyrimidinyl-(2) 1 -3 amino-5 -ethylarnino- (1,2,4) -triazole,

1- [4,6-dimethylpyrimidinyl-(2) 1-3 amino-5-butylamino- (1,2,4) -triazole,

1- [5 -bromopyrirnidinyl- (2) 1 guanazol 1- [S-bromopyrimidinyl- (2) 1-3 -amino-5 -methyla-mino-( 1,

2,4) -triazole,

1- [S-bromopyrimidinyl- (2) 1-3-amino-5-ethylamino-( 1,2,

4) -triazole,

1- [5 -bron1opyrimidinyl-(2) 1-3 -amino-S-isopropylamino- 1,2,4) -triazole,

1- [5 bromopy-r imidinyl- (2) 1 -3-amino-5- butylamino-( 1,2,

4) -triazole,

1- 5-chloropyrimidinyl-(2) 1 guanazole,

1- [pyrimidinyl-(Z) 1 -3-amino-5-anilino-( 1,2,4) -tniazole,

1- [4-methylpyrimidinyl- (2) 1-3 amino-5 -anilino-( 1,2,4)

triazole,

1- [4,6-dimethylpy-rimidinyl- (2) 1 -3-a.mino-5-anilino-( 1,2,

4 -tniazole,

1- [pyrimidinyl-(2) ]-3-anilino-5-amino-( 1,2,4) -triazole,

1- [pyrimidinyl- (2) 1-3-p-rnethoxyanilino-5-amino-( 1,2,4)

triazole,

1- [pyrimidinyl-(Z) 1-3-p-ethoxyanilino-5 aamino-( 1,2,4)

triazole,

1- [pyrimidinyl-(Z) 1-3-o-methoxyanilino-5-amino-( 1 ,2,4

tniazole,

1- [pyrirnidinyl-( 2) 1 -3,5 -di-anilino-( 1,2,4) -triazole,

1- [pyrimidinyl- (2) 1-3 -p-chloroan-ilino-5-methylarnino-( 1,

2,4 -tr ia-zole,

1- [pyrimidinyl- (2) 1 3 -p-chloroanilino-5 -ethylamino- 1,2,

4 -triazole,

1- [pyrirnidinyl- (2) 1-3-p-chloroanilino-S-isopropylamino- 1,2,4) -triazole,

1- [pyrimidinyl- 2) 1 -3 -p-chloroanilin -5 -butylamino-( 1,

2,4) -triazole,

1- [4-methylpyrimidinyl- (2) 1 -3 -p-chloroanilino- -methylamino- 1 ,2 ,4) -1riazole,

1- [4-met hylpyrimidinyl-(2) 1 -3 -p-chloroanilino-5-ethyl- =amin0-( 1,2,4) -triazole,

l [4-methylpyrimidinyl- (2 1 -3-p-chloro anil-ino-S sisopropylamino-( 1,24) -triazole,

1- [4-methylpyrimidinyl-(2) 1 -3-p-chloroanilino-5-butylamino-( 1,2,4) atriazole,

1- [4-methylpyrimidinyl- 2) 1-3 -anilino-5-amino-( 1,2,4)

triaL-ole,

1- [4,6-dimethylpynimidinyl- (2) 1-3 -anilino-5-amino-( 1,2,

4) -triazole, etc.

The mechanism of the reaction between the compound (II) and the compound (II'I) apparently is such that the hydrazine group of the hydrazinopyrimi-dines (TI) may react with the cyano group substituted derivatives (III) to form intermediates temporarily in a form, of biguanides, and then one mole of ammonia may be eliminated from the intermediates which, at the same time, may intramolecularly form the guanazole ring to give the objective pyrimidinylguanazoles (I).

The hydrazinopyrimidines (I) as the starting material may be in a form of salt formed with an inorganic or organic acid as mentioned below. The reaction proceeds more smoothly in the presence of a suitable acid substance, tor example, an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., a sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, propanesulfonic acid, toluenesulfonic acid, benezenesulfonic acid, etc., may generally be used. However, when the starting hydrazinopyrimidines are used in the form of a salt with such an acid as enumerated above, it is unnecessary to further add such an acid as the catalyst and the reaction proceeds smoothly even without addition of any acid substance.

It is desirable that this reaction is effected in a suit-able solvent. As the solvent, for example, water, a lower aliphatic alcohol such as methanol, ethanol, etc., an ether such as dioxane, tetrahydrofuran, etc., a tertiary amine such as pyridine, trimethylamine, etc., or a mixture of two or more kinds of them may usually be employed. The solvent to be used for the reaction is not necessarily the one capable of fully dissolving the starting materials, but it may be selected from those giving no hindrance to the objective reaction. In most cases, these reactions are preferably effected by heating the reaction mixture for several hours at a temperature of from 60 to 130 C., preferably around 100 C. It is, however, not wise to be bound to a temperature around 100 C., because the reaction may sometimes be favorably carried out at a temperature fairly lower or higher than 100 C.

The objective compounds (I) may also be synthesized by the condensation reaction in which a 2-ha1opyrimidine compound (IV) is allowed to react with guanazole compound (V).

This reaction is also effected usually in a solvent. As the solvent, for example, water, such a lower alcohol as methyl alcohol, ethyl alcohol, butyl alcohol, etc., such a ketone as acetone, methyl ethyl ketone, etc., such an ether as dioxane, tetrahydrofuran, etc., such an acetic acid ester as ethyl acetate, methyl acetate, etc., such a basic solvent as pyridine, picoline, collidine, triethylamine, dimethylforrnamide, etc., and such an aromatic solvent as benzene, toluene, chlorobenzene, etc., or a mixture of two or more kinds of them may be employed.

of dicyandiamide or its N- p In this reaction, too, it is not necessary for the solvent to be able to fully dissolve the starting materials, and the solvent may be selected from those giving no hindrance to the said reaction.

The reaction may be accelerated in the presence of a basic substance and, as the basic substance, for example, an inorganic alkaline substance such as an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogen carbonate, ammonia, ammonium carbonate, etc., such a tertiary amine as pyridine, collidine, picoline, trimethyl amine, triethyl amine, dimethylficrmamide, etc. or such a basic anion exchange resin as Amberlite IRA-400 (produced by Rohm & Ham Co., U.S.A.), Amberlite IRA-410 (produced by Rohm & Haas Co., U.S.A.), De- Acidite FF (produced by The Permutit 00., London, England), Dowex 1 (produced by Dow Chemical Co., U.S.A.), Dowex 2 (produced by Dow Chemical Co., U.S.A.), Duolite 42 (produced by Chemical Process Co., U.S.A.), etc. may favorably be utilized. When the basic substance, especially in a state of liquid, is employed as the solvent for the reaction, it is of course unnecessary to further add any basic substance as a reaction acceleratorl It may also be possible to cause an acid substance to catalyze the reaction. As the acid substance, for example, i such a mineral acid as hydrochloric acid, hydrobromic 1 acid, sulfuric acid, nitric acid, phosphoric acid, etc., such 1 an organic sulfonic acid as methane sulfonic acid, benzene 1 sulfonic acid, toluene sulfonic acid, etc., or such a cation- 1 exchange resin as Amberlite IR- (Rohm & Haas Co, U.S.A.), Chempro C-20 (Chemical Process 00., U.S.A.), Dowex 50 (Dow Chemical Co., U.S.A.), Permutit Q (Permutit A.G., Germany), Zeo-Karb 225 (The Permutitl Co., England), etc. may be employed.

Some of the compounds (I) may also be synthesized by allowing a l-guanylguanazole of the Formula VI to react with such a 1,3-bis-iunctionated compound as acetylacetone, propargylaldehyde, 1,1,3,3-tetraethoxypropane, lacetyl-2,2-diethoxypropane, 1 acetyl-Z-iminopropane, 1- acetyl-2,2-dich1-oropropane, 1-acetyl-2-hydroxyprop-l-ene,

2-acetyl-3-ethoxybut-2-ene, l-acetyl-Z-propoxyprop-l-ene,

hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.

Heating of the reaction mixture is usually unnecessary to eiTect the reaction. If there is a fear that the bond between the nitrogen atom in the 1,2-4-triazole-ring and the carbon atom of the guanyl group may be hydrolyzed in the reaction mixture, the reaction mixture may be cooled during the reaction, at least for a while just after the start of the reaction.

When the product of the above-mentioned condensation reactions is unsubstituted at the 3- and/or S-amino groups in the gu'anazole moiety, in other words, when R and/or R of the product are hydrogen, the product may further be acylated, if desired, in a usual manner for 'acylation, for example, with chlorides, bromides or anyhydrides of the carboxylic acid corresponding to the acyl group desired to be introduced into the amino group or groups. The carboxylic acid is usually such an aliphatic or an arylaliphatic carboxylic acid as acetic acid, formic acid, propionic acid, butyric acid, succinic acid, pimeric acid, monochloroacetic acid, phenylacetic acid, etc. The acid halides or the acid anhydrides may be used as usual together such a base as an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogen carbonate, ammonia, pyridine, picoline, dimethylformamide, etc.

These products which are fairly strong bases and capable of forming salts with a variety of acids, may be allowed to form the corresponding salts by neutralization with a strong acid as desired, for example, with such an inorganic acid as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or with such a sulfonic acid as methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc. These salts are also non-toxic and are more neutral and more soluble in water than the corresponding pyrimidinylguanazole bases, so that these salts may conveniently be used as medicines for the same purpose as the bases, especially favorably as injections.

This invention will now be described in further particularity by means of the following examples. It will be understood, of course, that the invention is not limited to the particular embodiments. In these examples, temperatures are all uncorrected, and the relationship between part by weight and part by volume is the same as that 1 between gram and milliliter.

Example I Example 2 Into 50 parts by weight of pyridine were added 11.4 parts by weight of 2-hydrazino-4,d-dimethylpyrirnidine and the mixture was boiled for 30 minutes to cause rehydrochloride and 55 parts by weight of dicyandiamide,

' 1- 5 -chloropyrimidiny1- 2) ]guanazole.

plates melting at 173 action to take place. After cooling, resulting precipitate were collected and recrystallized from water to obtain 5.4 parts by weight of 1-[4,6-dimethylpyrimidinyl-(2)]- guanazole as plate crystals which decompose at 297 C.

Example 3 Into 50 parts by weight of pyridine were added 6.4 parts by weight of 2-hydrazino-4-methylpyrimidine hydrochloride and 3.38 parts by weight of dicyandiamide, and the mixture was boiled for 5 hours to cause reaction to take place. The resultant mixture was concentrated under reduced pressure to remove pyridine, and the residue was recrystallized from diluted ethyl alcohol to obtain 2.7 parts by weight of l-[4-methylpyrimidinyl-(2)]guanazole which melts at 255 C.

Example 4 7 parts by weight of 2-hydrazine-S-bromopyrimidine were dissolved in hydrochloric acid, andthe solution was concentrated to dryness to give the corresponding hydrochloride. The so-obtained hydrochloride and 3.1 parts by weight of dicyandiamide were added to 70 parts by weight of pyridine, and the mixture was boiled for 5.5 hours, and then concentrated under reduced pressure. The residue was treated with diluted ethyl alcohol to precipitate crystals of 1-[5-bromopyrimidinyl-(2)Jguanazole. The crystals were collected by filtration and recrystallized from diluted ethyl alcohol to obtain 4.9 parts by weight of colorless crystals melting at a temperature higher than 300 C.

2-hydrazino-S-bromopyrirnidine employed in this example is a hitherto unknown compound and forms colorless needles melting at 205-206 C., and is synthesized, for example, as follows:

2-amino-S-bromopyrimidine is nitrified with nitric acid in concentrated sulfuric acid to obtain 2-nitroamino-5- bromopyrimidine, which is a novel compound forming plate crystals melting at 189 C., and the product thus obtained is then allowed, as the intermediate compound in the synthesis, to react with hydrazine hydrate under heating to obtain the Z-hydrazino compound.

Example 5 Hydrochloric acid was added to 7.3 parts by Weight of 2-hydrazino-5-chloropyrimidine, and the solution was concentrated to dryness to obtain the corresponding hy drochloride. Into 70 parts by weight of pyridine were added the above-obtained hydrochloride and 4.2 parts by weight of dicyandiamide, and the mixture was boiled for 5 hours. The resultant mixture was concentrated and the concentrate was cooled to precipitate the crystals of i The crystals were collected by filtration and recrystallized from diluted ethyl alcohol to obtain 4.1 parts by weight of colorless crystals melting at a temperature higher than 280 C.

Z-hydrazino-5-chloropyrimidine employed in this example is a novel compound having been first synthesized by the present inventors and forms colorless needles melting at 1805-182 C., and is synthesized, for example, as follows:

2-amino-S-chloropyrimidine is nitrified with nitric acid in concentrated sulfuric acid to give 2-nitroamino-5-chloropyrirnidine which is also novel and forms colorless C. with decomposition. This to react with hydrazine hydrate compound.

compound is then allowed to obtain the Z-hydrazino Example 6 Into 20 parts by volume of water were added 4 parts by weight of 2-chloro-4-methylpyrimidine, 3.4 parts by weight of guanazole and 1.65 parts by weight of anhydrous sodium carbonate, and the mixture was boiled for 8 hours to cause reaction to take place. After cooling, resulting precipitates were collected and recrystallized from ethyl alcohol to obtain 1.7 parts by weight of lroom temperature.

"7 [4-methylpyrirnidinyl( 2) ]guanazole as irregular prismatic crystals which melt at 252-253 C.

Instead of 1.65 parts by weight of anhydrous sodium Carbonate used in this example, 2.62 parts by weight of sodium hydrogen carbonate or 2.15 parts by weight of potassium carbonate was employed to give a similar result.

Example 7 Into 20 parts by volume of water were added 4 parts by weight of 2-chloropyrimidine, 3.8 parts by weight of guanazole and 1.9 parts by weight of anhydrous sodium carbonate, and the mixture was boiled for hours to cause reaction to take place. The resultant mixture was concentrated under reduced pressure to dryness, and the residue was extracted with 100 parts by volume of hot ethyl alcohol. The ethyl alcohol solution was concentrated to dryness, and the residue was recrystallized from water to obtain 1.5 parts by weight of 1-[pyrimidinyl (2)]guanazole as pillar crystals which melt at 244- 245 C.

Example 8 Into parts by volume of water were added 4 parts by weight of 2-chloro-4,o-dimethylpyrimidine, 2.8 parts by weight of guanazole and 1.5 parts by weight of anhydrous sodium carbonate, and the mixture was boiled for '8 hours to cause reaction to take place. After cooling, precipitates were collected and recrystallized from water to obtain 1.2 parts by weight of 1-[4,6-dimethylpyrimidinyl(2)-]guanazole as plates which decompose at 297- 298 C.

Example 9 Into 20 parts by volume of water were added 4 parts by weight of 2-chloro-4,6-dimethylpyrimidine, 2.8 parts by weight of guanazole and 0.5 part by volume of 35%- 35% hydrochloric acid.

Example 10 To 20 parts by weight of concentrated hydrochloric acid was added 10 parts by weight of nitric acid salt of l-guanylguanazole and into the mixture was gradually dropped 2.5 parts by weight of propargyl aldehyde under cooling and agitation. After completing the addition, agitation was further continued for several hours,

and the mixture was allowed to stand overnight and then concentrated at a low temperature. The residue was supplied with water and neutralized with sodium carbonate to separate crystals. The crystals were collected and recrystallized from water to obtain 3.8 parts by weight of l-[pyrimidinyl-(Z) lguanazole as colorless pillars melt ing at 244245 C.

' Example 11 To 80 parts by volume of ethyl alcohol saturated with hydrogen chloride was added 10 parts by weight of hydrochloric acid salt of l-guanylguanazole, and 12.5 parts by weight of 1,1,3,3-tetraethoxypropane was gradually dropped into the ethyl alcohol mixture with agitation under ice-cooling. After completing the addition, the agitation was continued for further several hours at a The mixture was allowed to stand overnight and then concentrated at a low temperature. The residue was supplied with water and neutralized with sodium carbonate to become weakly acid, whereupon crystals precipitated. The crystals were recrystallized from water to obtain 3 parts by weight of l-[Pyrimidinyl- (2) Iguanazole as colorless pillars melting at 214-245 C.

Example 12 Into 100 parts by volume of ethyl alcohol containing a little amount of hydrochloric acid were added 10 parts by weight of hydrochloric acid salt of l-guanylguanazole and 5 parts by weight of acetylacetone. The mixture was stirred for several hours at a room temperature, and then warmed at a temperature of about 50 C. for 10 hours. The reaction mixture was concentrated, and the residue was supplied with water and then neutralized to separate out precipitates of 1-[4,6-dimethylpyrimidinyl- (2)]guanazole, which were collected by filtration. The product forms colorless plates decomposing at 297 C. The yield, 2.2 parts by weight.

Example 13 Into 30 parts by volume of a mixture of equal amounts of water and ethyleneglycol monoethylether were added 5.6 parts by weight of 2-chloro-4-rnethyl-6-methoxypyrimidine and 3.5 parts by weight of guanazole, and the mixture was boiled for 7 hours to cause reaction to take place. The reaction mixture was concentrated to dryness and the residue was dissolved in a little amount of water. The solution was rendered alkaline by the addition of an aqueous solution of sodium hydroxide to separate out crystals. The crystals were recrystallized from diluted ethyl alcohol to obtain 1.2 parts by weight of l-[4-methyl-6-methoxypyrimidinyl-(2)]guanazole as colorless needles melting at 252254 C.

Example 14 Example 15 To 15 parts by volume of acetic acid anhydride was added 2 parts by weight of 1-[pyrimidinyl-(2) l guanazole, and the mixture was boiled for 10 minutes. The reaction mixture was ice-cooled, and insoluble crystals collected by filtration were recrystallized from water to obtain 1.2 parts by weight of 1-[pyrimidinyl-(2)]-3- acetamido-5-amino-(1,2,4)-triazole as pillar crystals melting at a temperature higher than 300 C.

Example 16 A mixture of 1 part by weight of l-[pyrimidinyl-(2) guanazole and 1.5 parts by weight of succinic acid was heated for 5 minutes on a bath of ll85 C. Then, to the reaction mixture was added 20 parts by volume of water and the mixture was boiled for a while, and then cooled. Insoluble'substances were collected by filtration to obtain 1.6 parts by weight of 1-[pyrimidinyl-(2)]- 3-succinylamino-5-amino- 1,2,4) -triazole monohydrate, which was recrystallized from water to give colorless needles melting at 250252 C.

Having thus disclosed the invention, we claim:

1. A compound of the formula,

N R1 mNN R2 N L RBHN N NHR4 wherein each of R and R is a member selected from the group consisting of hydrogen, lower alkyl and lower} alkoxyl, R is a member selected from the group consisting of hydrogen, halogen, lower alkyl and lower 8. 1-[4-methy1pyrimidiny1- (2)] 3 amino-5-anilinoalkoxy, and each of R and R is a member selected from 1,2,4)-triazole. the group consisting of hydrogen, lower alkyl, acetyl, 9. 1 [pyrimidinyl (2)] 3 acetamino 5 aminosuccinyl, phenyl, p-loweralkoxyphenyl, o-methoxyphenyl (1,2,4)tr1'azole. and p-halophenyl. 5 10. 1 [pyrimidinyl (2)] 3 succinylamino 5- 2. 1 [pyrimidinyl-( 2) Jguanazole. amino-(1,2,4)-triazole 3. 1-[4-methylpyrimidinyl-(2)Iguanazole.

4. 1-[4,6-dimethylpyrimidiny1-(2)JgHaHaZOIe, References Cited in the file of this patent i-[g py g yl-ggl l UNITED STATES PATENTS 6. romopyrimi iny guanazo e. 10

7. 1-[4-methyl-6-methoxypyrimidinyl-(2)Jguanazole. 2295566 DAleho et a] Sept 1942 UNITEDCSTATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,041,339 June 26 1962 Kenzo Sirakawa et a1.

It is hereby certified that error appears in the 813031;! numbered petent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, llnes 17 to 22, the left-hand portion of the formula,

should appear as shown below instead of as in the patent:

3 column 4, lines 2 and 3, for "benezenesulfonic" read benzenesulfonic Signed and sealed this 27th day of November 1962.

SEAL) ON C JOHNSOljfiJR DAVID LADD tteeting Officer Commissioner of Patents 

1. A COMPOUND OF THE FORMULA, 